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Título

MICROCEPHALY WITH PONTINE AND CEREBELLAR HYPOPLASIA (MICPCH): ATYPICAL PRESENTATION IN FEMALE

Apresentação do caso

LSLLMRG, female, 7 years old, presented with microcephaly and global hypotonia at birth, evolving to spastic tetraparesis. He started difficult-to-control epileptic seizures at 3 years of age. Skull MRI showed pontocerebellar hypoplasia. Mother with a history of two previous miscarriages, with pregnancy complicated by bleeding. She was born at term, Apgar 9/10, evolving with difficulty in sucking and low weight gain in the first month, in addition to significant delay in developmental milestones. Exome collected in 2020 showed a variant of uncertain significance in heterozygosity in the CASK gene (Microcephaly with pontine and cerebellar hypoplasia - MICPCH - OMIM #300749), associated with very rare variants identified in the ARID1A and TBX1 genes, related to phenotypes partially overlapping with the one described in the case index. Genetic evaluation of the parents did not point to similar pathogenic variants.

Discussão

Microcephaly with pontine and cerebellar hypoplasia (MICPCH) is a condition generally associated with pathogenic loss-of-function variants in CASK gene. CASK pathogenic variants MICPCH is typically seen in females with moderate-to-severe intellectual disability, progressive microcephaly with or without ophthalmologic anomalies, and sensorineural hearing loss. Most are able to sit independently; 20%-25% attain the ability to walk; language is nearly absent in most. Neurologic features may include axial hypotonia, hypertonia/spasticity of the extremities, and dystonia or other movement disorders. Nearly 40% have seizures by age ten years. Behaviors may include sleep disturbances, hand stereotypies, and self biting. MICPCH in males may occur with or without severe epileptic encephalopathy in addition to severe-to-profound developmental delay. When seizures are present they occur early and may be intractable. Dysmorphic features include overall poor growth, severe microcephaly, broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism. At 2013, a total of 130 individuals (45 males and 85 females) with MICPCH have been reported to date, the eldest of whom is age 25 years.

Comentários finais

This is a rare case of a de novo mutation in a female patient with an unusual presentation, evolving with early epileptic encephalopathy and more commonly seen in males. The mother's gestational history is remarkable. Parental screening and genetic counseling is of great importance in these cases.

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Não

Área

Neurogenética